Alzheimer's disease (AD) is a progressive and degenerative dementia (Terry, et al. (1991) Ann. Neurol. 30(4):572-80; Coyle (1987) in Encyclopedia of Neuroscience, Ed. G. Adelman, pp 29-31, Birkhäuser: Boston-Basel-Stuttgart), which in its early stages manifests primarily as a profound inability to form new memories (Selkoe (2002) Science 298(5594):789-91). Prominent neuritic plaques and neurofibrillary tangles have been suggested as the major pathology in brain tissue samples taken at autopsy from a demented patient. However, in spite of the prevalence of plaques, clinical and pathology studies suggest that plaques and fibrils were not responsible for cognitive deficits in AD. For example, careful analysis of plaque number and location revealed little or no correlation with nerve cell loss and cognitive impairment (Terry, et al. (1991) Ann. Neurol. 30(4):572-80; Terry, et al. (1999) “Alzheimer Disease”, 2nd Edition, Lippincott Williams & Wilkins: Philadelphia, Pa.; McLean, et al. (1999) Ann. Neurol. 46(6):860-6; Hibbard & McKeel, Jr. (1997) Anal. Quant. Cytol. Histol. 19(2):123-38; Sze, et al. (1997) J. Neuropathol. Exp. Neurol. 56(8):933-44), and analysis of total amyloid load showed little correlation with disease severity (Giannakopoulos, et al. (2003) Neurology 60(9):1495-500). As transgenic mouse models capable of substantial amyloid β (Aβ) 1-42 overproduction emerged, it became clear that significant behavioral deficits developed in these mice long before Aβ deposits or plaque pathology appeared. The parameter that correlated best with behavioral deficits was synaptic deterioration, a process with no apparent link to plaques or Aβ deposition (Mucke, et al. (2000) J. Neurosci. 20(11):4050-8; Hsia, et al. (1999) Proc. Natl. Acad. Sci. USA 96(6):3228-33; Kawarabayashi, et al. (2001) J. Neurosci. 21(2):372-81; Ashe (2005) Biochem. Soc. Trans. 33(Pt. 4):591-4).
Plaque-independent functional deficits have been suggested (Oda, et al. (1995) Exp Neurol. 136(1):22-31), wherein soluble Aβ complexes are the relevant molecular pathogens in AD, rather than Aβ fibrils. Such complexes are generated by mixing small amounts of clusterin (apoJ) with aqueous solutions of Aβ 1-42, resulting in substantially reduced fibril formation. The disconnection between amyloid fibrils and neurotoxicity was established with the isolation, characterization, and analysis of neurotoxic soluble oligomeric assemblies of Aβ 1-42 (U.S. Pat. No. 6,218,506; Lambert, et al. (1998) Proc. Natl. Acad. Sci. USA 95(11):6448-53), also referred to as amyloid-β derived diffusible ligands (ADDLs).
Soluble oligomeric assemblies of Aβ 1-42 assemble from relatively low concentrations of Aβ 1-42, and block LTP in intact animals or in hippocampal slice cultures (Lambert, et al. (1998) Proc. Natl. Acad. Sci. USA 95(11):6448-53; Wang, et al. (2002) Brain Res. 924(2):133-40; Wang, et al. (2004) J. Neurosci. 24(13):3370-8). These oligomeric assemblies exert their memory-compromising activity, at least in part, by binding specifically to dendritic spines on hippocampal neurons (Lacor, et al. (2004) J. Neurosci. 24(45):10191-200) and they elevate phosphorylation of tau at AD-specific epitopes (Shughrue, et al. (2005) 2005 Abstract Viewer/Itinerary Planner Program No. 209.16 Washington, D.C.: Society for Neuroscience). Soluble oligomeric assemblies of Aβ 1-42 are substantially elevated in AD brain (Gong, et al. (2003) Proc. Natl. Acad. Sci. USA 100(18):10417-22) and in cerebrospinal fluid from AD-diagnosed individuals (Georganopoulou, et al. (2005) Proc. Natl. Acad. Sci. USA 102(7):2273-6), providing evidence that ADDLs are the relevant molecular pathogens in AD.
As the likely molecular cause of AD, soluble oligomeric assemblies of Aβ 1-42 represent the optimal target for therapy or prophylaxis of AD, mild cognitive impairment, Down's syndrome and other related diseases such as stroke-associated memory loss and the like. Therefore, there is a need in the art for agents which modulate the assembly or activity of soluble oligomeric assemblies of Aβ 1-42.